Inherited risk of adenomatous polyps and colorectal cancer

Inherited susceptibility is an important factor in the pathogenesis of colorectal adenomas and cancer. Conditions with extreme susceptibility include two well-described autosomal dominant forms of hereditary colorectal cancer, familial adenomatous polyposis (FAP) caused by germ-line mutations of the adenomatous polyposis coli (APC) gene located on chromosome 5q2, and hereditary nonpolyposis colorectal cancer (HNPCC), due to mutations of the mismatch-repair genes. FAP and HNPCC account for less than 6% of colorectal cancer cases: familial clustering is common in the remainder of cases, which are often defined as 'sporadic', but which probably arise, in part, from an inherited susceptibility. Most of these familial cases can be stratified by severity: a relative with colorectal cancer diagnosed under the age of 50 or two or more first-degree relatives with colon cancer confer a risk up to 6- fold that for the general population. It has recently been shown that among asymptomatic individuals, those who have only one first-degree relative with colorectal cancer have a nearly two-fold increased risk of developing colorectal adenomas, and indications exist that the presence of such a family history is associated with a significant increase in the incidence and the recurrence rates of adenomatous polyps over a three-year period.